We propose to elucidate pathways of genes that lead from early causes to later defects in Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel genetic pathways by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drug targets by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.

Statement of Benefit to California:

Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drug targets to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches.

Review Summary:

The goal of this Fundamental Mechanisms proposal is to elucidate pathological mechanisms of Alzheimer’s Disease (AD) using induced pluripotent stem cells (iPSC) models derived from patients with aggressive, hereditary forms of this disorder. Building on a previous body of observations, the applicant seeks to identify key genes and pathways that lead from early defects in affected neurons to the hallmark phenotypes of end stage AD brain pathology. In addition to exploring the role of candidate genes and a key family of regulators in this process (Aims 1 and 2), the applicant plans to test the influence of other supporting brain cells on the development of neuronal pathology (Aim 3).
Significance and Innovation
- The proposal addresses a highly significant area of research. AD is a major neurodegenerative disease of the elderly for which there are currently no effective therapies, and for which the pathological underpinnings are poorly understood.
- The project tests several novel hypotheses about AD onset and while risky, could have a major impact on our understanding of the underlying mechanisms of AD. Even if relevant new gene/pathways are not discovered, reviewers were confident that novel data would be obtained.
- Although all three aims pose interesting questions, the rationale to connect them is not clearly articulated, especially with respect to Aim 3.
Feasibility and Experimental Design
- The applicant provides solid preliminary data to support the capabilities of the team for conducting the proposed experiments.
- As acknowledged by the applicant, there is some risk that the list of candidate genes and pathways to be screened in Aim 1 will be missing important players in the development of AD pathology. Reviewers agreed, however, that the number to be screened is appropriate and achievable, and that the choice of candidates is well supported.
- The research environment is appropriate for successful completion of the proposed studies.
- Aim 3 is somewhat underdeveloped due to its dependence on earlier aims, and the vague description afforded to rationale and experimental design. Despite these concerns, reviewers found the approaches to be clever, and they were convinced of the need to investigate more complex cellular environments for their role in the development of AD pathology.
- It will be important to carefully consider how the stage of disease progression in the patients from whom cells were derived might impact the outcomes of the proposed studies.
Principal Investigator (PI) and Research Team
- The PI is a world-renowned, accomplished scientist with many relevant publications in top tier journals. He/she is highly qualified to lead the project and has committed an appropriate level of effort.
- An experienced and well-balanced research team has been recruited to this endeavor.
Responsiveness to the RFA
- The application is responsive, using human iPSC-derived cells to gain novel insights into disease mechanisms.
- The AD patient iPSC lines to be utilized have already been derived and a phenotype has been described.